Composite dosage forms having an inlaid portion

ABSTRACT

A dosage form comprises at least one active ingredient, a first portion which comprises an exterior surface and one or more cavities defining at least one interior surface having indentations and an exterior surface, and a second molded portion which is inlaid into the cavities of the first portion and has an exterior surface. The first and second portions are in contact at an interface, the second portion comprises a solidified thermoplastic material, and the second portion resides substantially conformally upon the indentations of the first portion. In another embodiment, a dosage form comprises at least one active ingredient, a core having an outer surface and a shell residing on at least a portion of the core outer surface, wherein the shell comprises a first shell portion and a second molded shell portion which is inlaid into the first shell portion. In another embodiment, a dosage form comprises at least one active ingredient, a core, and a shell having a first molded shell portion which is discontinuous, and a second molded shell portion which is continuous, such that the discontinuities of the first shell portion are due to the presence of the second molded shell portion, and the first and second shell portions are compositionally different.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] This invention relates to composite dosage forms such aspharmaceutical compositions. More particularly, this invention relatesto composite dosage forms comprising at least one active ingredient andhaving a first portion and a molded second portion which is inlaid.

[0003] 2. Background Information

[0004] Coated tablets, such as film coated tablets, sugar coatedtablets, gelcaps, and geltabs are used as solid oral dosage forms,having improved aesthetics, stability and swallowability compared touncoated tablets. It is particularly useful to provide unique aestheticfeatures to solid dosage forms to aid with their identification anddifferentiation in the marketplace. Film coatings and sugar coatings aretypically applied by spraying in a rotating pan, and while they may beformulated in a variety of colors, generally only one color can beapplied around the entirety of a tabet core. Gelcaps and geltabs havebeen prepared by dip-coating, enrobing, and shrink-fitting of capsuleshells onto the surface of a tablet core. These methods enable the useof multiple colors, however suffer from other limitations.

[0005] Film formulations for producing gelcaps and geltabs prepared viaenrobing methods such as those disclosed in U.S. Pat. Nos. 5,146,730 and5,459,983 typically comprises a water-based gelatin preparation havingabout 45% gelatin and about 9% plasticizer (glycerin and/or sorbitol) byweight. The plasticizer has been reported to play a critical role insuch formulations. Low ratios of plasticizer to gelatin result in abrittle coating around the tablet core, while high ratios result in agelatin coating around the tablet which is flexible and can be peeledfrom the tablet. If a gelatin coating that adheres to the product coreis desired, then gelatin formulations having by-weight compositions of40 percent to 60 percent gelatin, 5 percent to 12 percent plasticizer,35 percent to 50 percent water, and colorants and pigments in the rangeof 0.1 percent to 3 percent should be considered. Glycerin and sorbitolcan be used as single plasticizers or in combination with each other. Inaddition, other sugars and poly-hydroxy compounds can be used asadditives and plasticizers. If a tamper-evident gelatin-coated medicinetablet is the desired end product, then the ratio of plasticizer togelatin in the gelatin formulation should be in the range of about 1:5.The need for such plasticizers at such levels imparts limitations toenrobed dosage forms, including a propensity to absorb moisture, whichmay compromise the physical and chemical stability of the product, aswell adding cost to the formulation.

[0006] Another current method for forming a shell (or coating) on a core(or substrate) is that disclosed in WO 01/57144 which utilizes theprinciples of electrostatic deposition to form the coating. This methodsuffers from the limitation that at least one of the core or the shellmust incorporate one or more “charge control agents”, such as metalsalicylates, for example zinc salicylate, magnesium salicylate andcalcium salicylate; quaternary ammonium salts; benzalkonium chloride;benzethonium chloride; trimethyl tetradecyl ammonium bromide(cetrimide); and cyclodextrins and their adducts, in an amount fromabout 1% to about 10% by weight of the shell. Charge control agentsoften cause an unpleasant taste sensation, and additionally maydisadvantageously increase oxidation of the shell in which they areemployed.

[0007] Other limitations shared by conventional encapsulation andenrobing processes include high cost and complexity, limitations on thethickness of the coating or shell, and the creation of raised seamsbetween capsule halves and/or coatings. It would therefore be desirableto have dosage forms of the present invention, which have enhancedversatility for a number of applications, including dosage forms todeliver pharmaceuticals, nutritionals and/or confections, which may bein the form of geltabs or gelcaps, coated tablets, high potency dosageforms and the like. Moreover, such dosage forms have unique and pleasantaesthetic qualities that are valuable in the marketplace.

[0008] It is known to produce coatings on tablets by compression, toproduce either multiple stacked layers, or core and shellconfigurations. Such coatings may have shapes which are substantiallyindependent of the shape of the core, as disclosed for example in WO00/18447. Commercially available compression coating machines areavailable for example from Korsch America Inc. (a subsidiary of KorschAG), and described in WO 89/11968. Modified release dosage formsprepared via compression are exemplified in U.S. Pat. Nos. 5,738,874 and6,294,200, and WO 99/51209. It is possible via compression-coating toproduce a 2-portion shell, which may function as a barrier, or releasedelaying coating, however compression-coated systems are limited by theshell thickness and shell composition as well as processing costs.Gunsel et al., “Compression-coated and layer tablets” in PharmaceuticalDosage Forms—Tablets, edited by H. A. Lieberman, L. Lachman, J. B.Schwartz (2nd ed., rev. and expanded Marcel Dekker, Inc.) pp. 247-284,for example, discloses the thickness of compression coated shells istypically between 800 and 1200 microns. Additionally these authors notethat “the advent of film coating dissipated much of the advantage of drycoating since larger quantities of tablets can be coated in a short timewith film-formers dissolved in organic or aqueous solvents.” Typically,compressed coatings must contain a substantial amount of a compressiblematerial. The compressed shell of WO 00/18447, for example, employsmicrocrystalline cellulose at a level of about 30%.

[0009] Dosage forms having two or more distinct portions are useful inthe pharmaceutical arts for overcoming a number of commonly encounteredchallenges, including the separation of incompatible active ingredients,achieving acceptable content uniformity of a low-dose/high potencyactive ingredient, delivering one or more active ingredients in apulsatile manner, and providing unique aesthetic characteristics fordosage form identification. Known methods for achieving a multi-portionpharmaceutical dosage form include particle coating, multi-layertablets, compression-coating, and spray coating techniques. It is alsoknown for example in the household products industry to assemble solidforms from two or more different parts for the purpose of separatingactive ingredients, or delivering different active ingredients atdifferent times.

[0010] Dosage forms comprising coated particles are described forexample in U.S. Pat. No. 5,593,696, which describes oral dosage formsfor treating of gastric disorders. The dosage forms contain, as activeingredients, famotidine and sucralfate. In the dosage form, thefamotidine is present in the composition in particulate (granulate)form, and the particulate famotidine is provided with a protectivebarrier layer which prevents interaction between the famotidine and thesucralfate in the composition. The barrier layer is preferably apolymeric coat which dissolves partially in vivo in the stomach environsto release the coated famotidine. U.S. Pat. No. 5,980,944 describes asolid oral dosage form for the treatment of gastrointestinal disorderscomprising a therapeutically effective amount of a pharmaceuticalsuitable for the treatment of gastric disorders selected from the groupconsisting of granules of diphenoxylate, loperamide, loperamide-N-oxide,pharmaceutically acceptable salts thereof and combinations thereof, anda therapeutically effective amount of simethicone wherein thepharmaceutical and simethicone are separated by a barrier coat on thegranules which is substantially impermeable to simethicone.

[0011] Multi-layer tablets are described, for example, in U.S. Pat. No.5,200,193, which describes multi-layered pharmaceutical active tabletscomprising an immediate release layer and a homogeneous compressedsustained release layer comprising an erosion promoter, which uponadministration results in a long-lasting, slow and relatively regularincremental release of the pharmaceutical active ingredient. U.S. Pat.No. 6,372,252 describes a pharmaceutical sustained release formulationcapable of providing therapeutically effective bioavailability ofguaifenesin for at least twelve hours after dosing in a human subject.The modified release guaifenesin bi-layer tablet disclosed has a firstportion comprising an immediate release formulation of guaifenesin and asecond portion comprising a sustained release formulation ofguaifenesin. U.S. Pat. No. 4,999,226 discloses a multi-layered tabletcontaining an ibuprofen layer, a piperidino-alkanol antihistamine layer,and a layer or layers containing conventional pharmaceutical excipientswhich is interspersed between the ibuprofen and piperidino-alkanol layerand serves to physically separate them. This multi-layered tablet solvesthe problems associated with the physical and chemical incompatibilitiesbetween ibuprofen and the piperidinoalkanol antihistamines. U.S. Pat.No. 4,198,390 describes a tablet containing at least two separate anddiscrete volume portions, one of which contains simethicone and theother of which contains antacid. A barrier separates the two volumeportions to maintain the simethicone out of contact with the antacid andto prevent migration of the simethicone from its volume portion of thetablet into the volume portion containing the antacid, and vice versa.U.S. Pat. No. 5,133,892 describes a multilayer detergent tabletcontaining an outer layer, a barrier layer and an inner layer. Thetablet sequentially releases ingredients contained in the outer layerand ingredients contained in the inner layer. The time interval betweenthe release of the outer layer ingredients and the release of the innerlayer ingredients is controlled by the particular choice of aningredient for the barrier layer and the relative thicknesses of theinner layer, the barrier layer and the outer layer. The tablet is ableto separate in time the dissolution of incompatible ingredients such asan enzyme and a chlorine bleach. The tablet also provides sequentialrelease of a dishwashing composition and a rinse aid composition suchthat cleaning is accomplished prior to the release of the rinse aid.

[0012] Compression-coated tablets are useful for separation ofincompatible active ingredients, and for pulsatile release of one ormore active ingredients. Compressed coatings may have shapes which aresubstantially independent of the shape of the core, as disclosed forexample in WO 00/18447. Commercially available compression coatingmachines are available for example from Korsch America Inc., asubsidiary of Korsch AG, and described in WO 89/11968. Modified releasedosage forms prepared via compression are exemplified in U.S. Pat. Nos.5,738,874 and 6,294,200, and WO 99/51209. It is possible, viacompression-coating, to produce a 2-portion shell, which may function asa barrier, or release delaying coating; however compression-coatedsystems are limited by the shell thickness and shell composition as wellas processing costs. Gunsel et al., “Compression-Coated and LayerTablets” in Pharmaceutical Dosage Forms—Tablets, edited by H. A.Lieberman, L. Lachman, J. B. Schwartz (2nd ed., rev. and expanded MarcelDekker, Inc.) pp. 247-284, for example, discloses the thickness ofcompression coated shells is typically between 800 and 1200 microns.Additionally these authors note that “the advent of film coatingdissipated much of the advantage of dry coating since larger quantitiesof tablets can be coated in a short time with film-formers dissolved inorganic or aqueous solvents.” Typically, compressed coatings mustcontain a substantial amount of a compressible material. The compressedshell of WO 00/18447, for example, employs microcrystalline cellulose ata level of about 30%.

[0013] One method for addressing the challenge of low-dose/high potencyactives is described for example in U.S. Pat. No. 4,322,449 and U.S.Pat. No. RE 31764, which disclose a method for the preparation ofpharmaceuticals which comprises using a piezoelectric dosing system todot liquid, dissolved or suspended active substance onto apharmaceutical carrier. The disclosed method enables precise dosing ofactive pharmaceutical ingredients onto pharmaceutical carriers. Thedotting is effected by, for example, use of tubular or plate-shapedpiezoelectric dosing systems. However, the liquid, dissolved orsuspended active substance can also be divided into discrete droplets ofspecific volume after application of a high pressure during passagethrough a narrow nozzle, whereby the individual droplets aresuccessively charged electrically and are intermittently deflectedelectrostatically towards the pharmaceutical carriers.

[0014] The incorporation of molded portions into delivery systems hasbeen used in the household products industry to achieve an additionaldegree of versatility. Assembled forms comprising a mixture ofcompressed and molded portions are known for example for delivery ofdetergents. WO 01/49815 describes a composition for use in a dishwashercharacterized by a base composition in the form of a tablet whichbecomes active substantially during the main wash cycle, and at leastone separate zone in or on the tablet is provided with a substance thatbecomes active substantially during the rinse cycle of the dishwasher.One example of such assembled forms comprises a compressed tabletportion having a hemispherical indentation in a major face, and a moldedspherical portion fit into and adhered to the indentation in thecompressed portion. One limitation of such assemblies is the propensityfor the two portions to become detached due to inadequate adherance andminimal surface area of contact between them. In such assemblies, themolded portion may be smaller than the indentation in the compressedportion, e.g. the diameter of the molded portion is at least about 20microns less that the diameter of the opening in the compressed portion.Alternatively, similar forms may be assembled by press-fitting. In theseforms the dimensions of the molded portion and the opening in thecompressed portion may be similar. Such assemblies are additionallylimited in the types of geometries that are possible at the interface.In press-fit assemblies, the width of the molded portion at the deepestpart of the interface may not be substantially larger than the width ofthe opening through which it must be fit. In other words the draft anglebetween the outer and inner surfaces of the compressed portion may notbe negative. Moreover, the interface or area of contact between the twoportions may not form an interlock.

[0015] Another significant opportunity in designing pharmaceuticaldosage forms is that of product identification and differentiation. Itis useful, both from a consumer safety perspective, and a commercialperspective, to have a dosage form with a unique appearance that isreadily recognizable and identifiable.

[0016] Current techniques for providing unique dosage formidentification include the use of intagliations. Intagliations areimpressed marks typically achieved by engraving or impressing of agraphical representation, for example a figure, mark, character, symbolsuch as a letter, a name, a logo, a pictoral representation, and thelike, or any combination thereof, in a tablet or other solid dosageform, preferably by a punching procedure. U.S. Pat. No. 5,827,535, forexample, describes soft gelatin capsules having an external surfacehaving defined thereon an impressed graphical representation. U.S. Pat.No. 5,405,642 discloses a method of highlighting intagliations in whiteor colored coated tablets by spraying onto said tablets a suspensioncomprising a filling material having a different color, a waxy materialand a solvent, and removing the solvent and the excess of fillingmaterial and waxy material. The suspension of U.S. Pat. No. 5,405,642comprises a waxy material and a filling material in a critical weightratio from about 1:3 to about 1:12. Too little waxy material will leadto insufficient bonding of the filling material; too much waxy materialthe filling material will bond too strongly to the tablet surface andconsequently will be difficult to remove afterwards. Suitable solventsfor the suspension of U.S. Pat. No. 5,405,642 are those solvents whereinthe filling material and, if present, the dye, do not dissolve. Forexample, non-dyed starches and celluloses may be suspended in alcohols,e.g. ethanol, isopropanol and the like, halogenated hydrocarbons, e.g.dichloromethane, trichloromethane and the like.

[0017] EP 060,023 discloses a method of emphasizing intagliations incolored (i.e. not white) solid articles, in particular tablets, bycoating the tablet surface and filling up the intagliations with acoating film comprising an optically anisotropic substance. An opticalcontrast between the tablet surface and the intagliations is obtained,presumably due to the different orientation of the optically anisotropicsubstance on the tablet surface and in the intagliations. The techniqueis limited to colored articles and only allows the use of opticallyanisotropic filling materials. The optical effect merely being based ona different contrast is not particularly clear.

[0018] EP 088,556 relates to a method of highlighting intagliations inwhite or colored tablets by contacting said tablets with a dry, powderymaterial having a different color than the tablet surface and thenremoving the excess powdery material not deposited in the intagliations.The powdery material is thought to adhere better to the intagliations ofcoated tablets than to those of uncoated tablets. Adherence can furtherbe increased by using a mixture of a wax and a powdery material as thedeposition material and heating the filled tablets to 40° C.-90° C. tomelt the wax. Finally, an outer coating may be applied to the filledtablets. However, the method disclosed in EP 088,556 has severalproblems. First, it has been found that the adhesion of the powderymaterial to the intagliations is not satisfactory as the material showsa tendency to loosen and fall out. This problem arises particularly whenan outer coating film is applied to the filled tablet and the loosenedmaterial becomes fixed in the outer coating film, thus yielding speckledtablets. Addition of a wax to the powdery material to improve adhesion,on the other hand, adversely affects the distribution of the powderymaterial in that more of it sticks to the surface of the tablet and isdifficult to remove. Several other drawbacks are associated with the useof a wax in the dry powdery material. In particular the necessity toheat the tablets filled with a wax and a powdery material to melt thewax poses a barely acceptable risk since many medicines are thermolabileand might deteriorate significantly in the process. Further, it isdifficult to evenly dye a dry mixture of a wax and a powdery material,which in turn puts a limitation on the effectively possible colorcombinations.

[0019] U.S. Pat. No. 4,139,589 describes a process for the manufactureof an inlaid tablet, comprising the steps of incorporating into aplastic chewing gum mass a sustained-release active ingredient;incorporating into a non-plastic tablet mass a substantiallyimmediate-release pharmaceutically active ingredient; and respectivelyconverting the chewing gum mass and the tablet mass into the core andthe outer layer of the inlaid tablet. A preferred embodiment includesconverting the tablet mass into a recessed preformed element, convertingthe chewing gum mass into the core, inserting the core into the recessof the preformed element, introducing the preformed element and the coreinto a tablet mold, and subjecting the preformed element and the core inthe mold to pressure.

[0020] All of the methods described above for producing a dosage formhaving one or more separate portions are relatively costly, complex, andtime-intensive. Additionally, known methods for producing filled-inintagliations are limited in terms of suitable materials and theobtainable surface configurations and appearance of the resultant dosageform. Besides the above-mentioned limitations on the fill materialitself, the tablet subcoating must be non-adhesive enough for thefill-in material to rub off upon tumbling in a hot coating pan. Thesemethods cannot produce filled-in intagliations having the fill materialraised above the tablet surface, or even perfectly flush with the tabletsurface. The prior art product can only have a fill-in material surfacethat is slightly depressed, abraided, or concave with respect to thetablet surface.

[0021] Another significant challenge in the pharmaceutical industry isthe opportunity to minimize manufacturing and packaging costs throughstandardization. Many drugs are available in several different strengthtablets for convenience of dosing different patients with varying needs.Typically, higher strength tablets have greater weight and larger sizethan tablets having lower amounts of active ingredient. Handling andpackaging costs could be reduced by having a dosage form design with theversatility to accommodate multiple different dosage amounts ofmedication in the same size tablet, yet be readily identifiable topatients and healthcare professionals in terms of identity and strength.

[0022] Accordingly, it is one object of this invention to provide acomposite form comprising at least one active ingredient, a firstportion and a second molded portion comprising a second material, inwhich the second material is inlaid and compositionally different thanthe first material.

[0023] Other objects, features and advantages of this invention will beapparent to those skilled in the art from the detailed description ofthe invention provided herein.

SUMMARY OF THE INVENTION

[0024] In one embodiment, the dosage form of this invention comprises atleast one active ingredient, a first portion which comprises an exteriorsurface and one or more cavities defining at least one interior surfacehaving indentations, and an exterior surface, and a second moldedportion which is inlaid into the cavities of the first portion and hasan exterior surface. The first and second portions are in contact at aninterface, the second portion comprises a solidified thermoplasticmaterial, and the second portion resides substantially conformally uponthe indentations.

[0025] In another embodiment, the second molded portion is substantiallyfree of pores having a diameter of 0.5 to 5.0 microns.

[0026] In another embodiment, the first and second portions are inintimate contact at the interface.

[0027] In another embodiment, the first portion is a compressed tablet.

[0028] In another embodiment, the first portion is a molded tablet.

[0029] In another embodiment, the first portion comprises anintagliation and the second portion resides in the intagliation.

[0030] In another embodiment, the exterior surface of the second portionis flush with the exterior surface of the first portion.

[0031] In another embodiment, the exterior surface of the second portionis raised with respect to the exterior surface of the first portion.

[0032] In another embodiment, the first portion consists essentially ofa single homogeneous layer.

[0033] In another embodiment, the second molded portion comprises atleast one active ingredient.

[0034] In another embodiment, the first portion has a first color andthe inlaid second portion has a second color.

[0035] In another embodiment, the first portion comprises a first activeingredient and the inlaid second portion comprises a second activeingredient which may be the same or different than the first activeingredient.

[0036] In another embodiment, the first and second portions togetherprovide a prearranged pattern.

[0037] In another embodiment, the first portion comprises amicroelectronic device.

[0038] In another embodiment, the interior surface of one or morecavities in the first portion has a draft angle having a value less thanzero.

[0039] In another embodiment, the interface is substantially coextensivewith the interior surface.

[0040] In another embodiment, the first portion is discontinuous and thesecond portion is continuous.

[0041] In another embodiment of this invention, the dosage formcomprises at least one active ingredient, a core having an outer surfaceand a shell residing on at least a portion of the core outer surface.The shell comprises a first shell portion and a second shell portion,and the second molded shell portion which is inlaid into the first shellportion, and the first and second shell portions are in contact at aninterface.

[0042] In another embodiment, the shell has an outer surface and thesecond molded shell portion extends from the outer surface of the coreto the outer surface of the shell.

[0043] In another embodiment, the first and second shell portions areboth discontinuous.

[0044] In another embodiment, the first shell portion is discontinuous,and the second shell portion is continuous.

[0045] In another embodiment, the first shell portion has a first colorand the second shell portion has a second color.

[0046] In another embodiment, the core comprises a compressed powder.

[0047] In another embodiment, the core comprises an insert.

[0048] In another embodiment, the insert comprises an active ingredient.

[0049] In another embodiment, one or more of the core, the inlaidportion or the insert comprise an active ingredient.

[0050] In another embodiment, the core comprises a microelectronicdevice.

[0051] In another embodiment, the insert comprises a microelectronicdevice.

[0052] In another embodiment, either the first shell portion, secondshell portion, or both have a textured outer surface.

[0053] In another embodiment, the outer surface of the shell contains aprearranged pattern.

[0054] In another embodiment, the shell comprises one or more openingstherein.

[0055] In another embodiment, the outer surface of the shell issubstantially smooth.

[0056] In another embodiment, the shell contains indentations, letters,symbols or a pattern.

[0057] In another embodiment, the first shell portion containsindentations, letters, symbols or a pattern.

[0058] In another embodiment, the second shell portion containsindentations, letters, symbols or a pattern.

[0059] In another embodiment, the first shell portion, second shellportion or both contain raised protrusions in the form of letters,symbols or a pattern.

[0060] In another embodiment, the inlaid portion is substantially freeof pores having a diameter of 0.5-5.0 microns.

[0061] In another embodiment, the second shell portion has a portionthereof having a draft angle having a value less than zero at theinterface.

[0062] In another embodiment of this invention, the dosage formcomprises at least one active ingredient, a core, and a shell having afirst molded shell portion which is discontinuous, and a second moldedshell portion which is continuous, such that the discontinuities of thefirst shell portion are due to the presence of the second molded shellportion, and the first and second shell portions are compositionallydifferent.

[0063] In another embodiment, the first and second shell portionscomprise a solidified thermoplastic material.

[0064] In another embodiment, the exterior surfaces of the first andsecond shell portions are colinear.

[0065] In another embodiment, the second molded portion has a portionthereof having a draft angle having a value less than zero.

[0066] In another embodiment, the cavities define a plurality of sidewalls for receiving the inlaid portion, and the side walls have a draftangle having a value less than zero.

[0067] In another embodiment, either the first portion, the secondportion, or both contain an active ingredient.

BRIEF DESCRIPTION OF THE DRAWINGS

[0068]FIGS. 1A and 1B depict an example of a dosage form of thisinvention.

[0069]FIGS. 2A and 2B depict another example of a dosage form of thisinvention, in which the core has a shell residing thereon which containsan inlaid portion.

[0070]FIGS. 3A and 3B depict the draft angle of a prior art compositionand an embodiment of this invention.

DETAILED DESCRIPTION OF THE INVENTION

[0071] In one embodiment of this invention, the dosage form comprises atleast one active ingredient, a first portion which comprises one or morecavities and indentations and an exterior surface, and a second moldedportion which is inlaid into the cavities of the first portion and hasan exterior surface. The first and second portions are in contact at aninterface, the second portion comprises a solidified thermoplasticmaterial, and the second portion resides substantially conformally uponthe indentations of the first portion.

[0072] As used herein, an “exterior surface” of a portion is a surfacethat comprises part of the exterior surface of the finished dosage form.

[0073] As used herein, the term “substantially conformally” refers tothe fact that the cavities of the first portion are defined by surfaceshaving peaks and valleys therein, and the second portion resides in thecavities and the second portion also has peaks and valleys in itssurfaces, such that the peaks and valleys of the surfaces of the secondportion correspond substantially inversely to the major peaks andvalleys of the surfaces defined by the cavities.

[0074] In another embodiment of this invention, the dosage formcomprises at least one active ingredient, a core having an outer surfaceand a shell residing on at least a portion of the core outer surface,wherein the shell comprises a first shell portion and a second shellportion, and the second molded shell portion which is inlaid into thefirst shell portion.

[0075] In another embodiment of this invention, the dosage formcomprises at least one active ingredient, a core, and a shell having afirst molded shell portion which is discontinuous, and a second moldedshell portion which is continuous, such that the discontinuities of thefirst shell portion are due to the presence of the second molded shellportion, and the first and second shell portions are compositionallydifferent.

[0076] As used herein, the term “compositionally different” means havingfeatures that are readily distinguishable by qualitative or quantitativechemical analysis, physical testing, or visual observation. For example,the first and second materials may contain different ingredients, ordifferent levels of the same ingredients, or the first and secondmaterials may have different physical or chemical properties, differentfunctional properties, or be visually distinct. Examples of physical orchemical properties that may be different include hydrophylicity,hydrophobicity, hygroscopicity, elasticity, plasticity, tensilestrength, crystallinity, and density. Examples of functional propertieswhich may be different include rate and/or extent of dissolution of thematerial itself or of an active ingredient therefrom, rate ofdisintegration of the material, permeability to active ingredients,permeability to water or aqueous media, and the like. Examples of visualdistinctions include size, shape, topography, or other geometricfeatures, color, hue, opacity, and gloss.

[0077] n certain embodiments the first portion consists essentially of asingle homogeneous layer. In other words, it may be a single moldedcomposition or a single compressed tablet. If the portion were dividedinto parts, each part would have the same density, porosity, color,crystallinity, etc.

[0078] As used herein, the term “dosage form” applies to any solidobject, semi-solid, or liquid composition, designed to contain aspecific pre-determined amount (i.e. dose) of a certain ingredient, forexample an active ingredient as defined below. Suitable dosage forms maybe pharmaceutical drug delivery systems, including those for oraladministration, buccal administration, rectal administration, topical,transdermal, or mucosal delivery, or subcutaneous implants, or otherimplanted drug delivery systems; or compositions for deliveringminerals, vitamins and other nutraceuticals, oral care agents,flavorants, and the like. Preferably the dosage forms of the presentinvention are considered to be solid, however they may contain liquid orsemi-solid components. In a particularly preferred embodiment, thedosage form is an orally administered system for delivering apharmaceutical active ingredient to the gastro-intestinal tract of ahuman. In another preferred embodiment, the dosage form is an orallyadministered “placebo” system containing pharmaceutically inactiveingredients, and the dosage form is designed to have the same appearanceas a particular pharmaceutically active dosage form, such as may be usedfor control purposes in clinical studies to test, for example, thesafety and efficacy of a particular pharmaceutically active ingredient.

[0079] Suitable active ingredients for use in this invention include forexample pharmaceuticals, minerals, vitamins and other nutraceuticals,oral care agents, flavorants and mixtures thereof. Suitablepharmaceuticals include analgesics, anti-inflammatory agents,antiarthritics, anesthetics, antihistamines, antitussives, antibiotics,anti-infective agents, antivirals, anticoagulants, antidepressants,antidiabetic agents, antiemetics, antiflatulents, antifungals,antispasmodics, appetite suppressants, bronchodilators, cardiovascularagents, central nervous system agents, central nervous systemstimulants, decongestants, diuretics, expectorants, gastrointestinalagents, migraine preparations, motion sickness products, mucolytics,muscle relaxants, osteoporosis preparations, polydimethylsiloxanes,respiratory agents, sleep-aids, urinary tract agents and mixturesthereof.

[0080] Suitable oral care agents include breath fresheners, toothwhiteners, antimicrobial agents, tooth mineralizers, tooth decayinhibitors, topical anesthetics, mucoprotectants, and the like.

[0081] Suitable flavorants include menthol, peppermint, mint flavors,fruit flavors, chocolate, vanilla, bubblegum flavors, coffee flavors,liqueur flavors and combinations and the like.

[0082] Examples of suitable gastrointestinal agents include antacidssuch as calcium carbonate, magnesium hydroxide, magnesium oxide,magnesium carbonate, aluminum hydroxide, sodium bicarbonate,dihydroxyaluminum sodium carbonate; stimulant laxatives, such asbisacodyl, cascara sagrada, danthron, senna, phenolphthalein, aloe,castor oil, ricinoleic acid, and dehydrocholic acid, and mixturesthereof, H2 receptor antagonists, such as famotadine, ranitidine,cimetadine, nizatidine; proton pump inhibitors such as omeprazole orlansoprazole; gastrointestinal cytoprotectives, such as sucraflate andmisoprostol; gastrointestinal prokinetics, such as prucalopride,antibiotics for H. pylori, such as clarithromycin, amoxicillin,tetracycline, and metronidazole; antidiarrheals, such as diphenoxylateand loperamide; glycopyrrolate; antiemetics, such as ondansetron,analgesics, such as mesalamine.

[0083] In one embodiment of the invention, the active agent may beselected from bisacodyl, famotadine, ranitidine, cimetidine,prucalopride, diphenoxylate, loperamide, lactase, mesalamine, bismuth,antacids, and pharmaceutically acceptable salts, esters, isomers, andmixtures thereof.

[0084] In another embodiment, the active agent is selected fromanalgesics, anti-inflammatories, and antipyretics: e.g. non-steroidalanti-inflammatory drugs (NSAIDs), including propionic acid derivatives:e.g. ibuprofen, naproxen, ketoprofen and the like; acetic acidderivatives: e.g. indomethacin, diclofenac, sulindac, tolmetin, and thelike; fenamic acid derivatives: e.g. mefanamic acid, meclofenamic acid,flufenamic acid, and the like; biphenylcarbodylic acid derivatives: e.g.diflunisal, flufenisal, and the like; and oxicams: e.g. piroxicam,sudoxicam, isoxicam, meloxicam, and the like. In a particularlypreferred embodiment, the active agent is selected from propionic acidderivative NSAID: e.g. ibuprofen, naproxen, flurbiprofen, fenbufen,fenoprofen, indoprofen, ketoprofen, fluprofen, pirprofen, carprofen,oxaprozin, pranoprofen, suprofen, and pharmaceutically acceptable salts,derivatives, and combinations thereof. In another embodiment of theinvention, the active agent may be selected from acetaminophen, acetylsalicylic acid, ibuprofen, naproxen, ketoprofen, flurbiprofen,diclofenac, cyclobenzaprine, meloxicam, rofecoxib, celecoxib, andpharmaceutically acceptable salts, esters, isomers, and mixturesthereof.

[0085] In another embodiment of the invention, the active agent may beselected from pseudoephedrine, phenylpropanolamine, chlorpheniramine,dextromethorphan, diphenhydramine, astemizole, terfenadine,fexofenadine, loratadine, desloratidine, doxilamine, norastemizole,cetirizine, mixtures thereof and pharmaceutically acceptable salts,esters, isomers, and mixtures thereof.

[0086] Examples of suitable polydimethylsiloxanes, which include, butare not limited to dimethicone and simethicone, are those disclosed inU.S. Pat. Nos. 4,906,478, 5,275,822, and 6,103,260, the contents of eachis expressly incorporated herein by reference. As used herein, the term“simethicone” refers to the broader class of polydimethylsiloxanes,including but not limited to simethicone and dimethicone.

[0087] The active ingredient or ingredients are present in the dosageform in a therapeutically effective amount, which is an amount thatproduces the desired therapeutic response upon oral administration andcan be readily determined by one skilled in the art. In determining suchamounts, the particular active ingredient being administered, thebioavailability characteristics of the active ingredient, the dosingregimen, the age and weight of the patient, and other factors must beconsidered, as known in the art. In one embodiment, the dosage formcomprises at least about 85 weight percent of the active ingredient.

[0088] In certain embodiments in which modified release of the activeingredient is desired, the active ingredient may optionally be coatedwith a release-modifying coating, as are well known in the art. Thisadvantageously provides an additional tool for modifying the releaseprofile of active ingredient from the dosage form. For example, thedosage form may contain coated particles of one or more activeingredients, in which the particle coating confers a release modifyingfunction, as is well known in the art. Examples of suitable releasemodifying coatings for particles are described in U.S. Pat. Nos.4,173,626; 4,863,742; 4,980,170; 4,984,240; 5,286,497; 5,912,013;6,270,805; and 6,322,819. Commercially available modified release activeingredients may also be employed. For example, acetaminophen particleswhich are encapsulated with release-modifying polymers by acoaccervation process may be used in the present invention.Coaccervation-encapsulated acetaminophen may be purchased commerciallyfrom Eurand America, Inc. (Vandalia, Ohio) or from Circa Inc. (Dayton,Ohio).

[0089] If the active ingredient has an objectionable taste, and thedosage form is intended to be chewed or disintegrated in the mouth priorto swallowing, the active ingredient may be coated with a taste maskingcoating, as known in the art. Examples of suitable taste maskingcoatings are described in U.S. Pat. No. 4,851,226, U.S. Pat. No.5,075,114, and U.S. Pat. No. 5,489,436. Commercially available tastemasked active ingredients may also be employed. For example,acetaminophen particles which are encapsulated with ethylcellulose orother polymers by a coaccervation process may be used in the presentinvention. Coaccervation-encapsulated acetaminophen may be purchasedcommercially from Eurand America, Inc. (Vandalia, Ohio), or from CircaInc. (Dayton, Ohio).

[0090] In embodiments in which the first portion is prepared viacompression, suitable excipients include fillers, binders,disintegrants, lubricants, glidants, and the like.

[0091] In embodiments in which the first portion is prepared viacompression, suitable fillers include water-soluble compressiblecarbohydrates such as sugars, which include dextrose, sucrose,isomaltalose, fructose, maltose, and lactose, polydextrose,sugar-alcohols, which include mannitol, sorbitol, isomalt, maltitol,xylitol, erythritol, starch hydrolysates, which include dextrins, andmaltodextrins, and the like, water insoluble plasticly deformingmaterials such as microcrystalline cellulose or other cellulosicderivatives, water-insoluble brittle fracture materials such asdicalcium phosphate, tricalcium phosphate and the like and mixturesthereof.

[0092] In embodiments in which the first portion is prepared viacompression, suitable binders include dry binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose, and the like; wet binderssuch as water-soluble polymers, including hydrocolloids such asalginates, agar, guar gum, locust bean, carrageenan, tara, gum arabic,tragacanth, pectin, xanthan, gellan, maltodextrin, galactomannan,pusstulan, laminarin, scleroglucan, gum arabic, inulin, pectin, whelan,rhamsan, zooglan, methylan, chitin, cyclodextrin, chitosan, polyvinylpyrrolidone, cellulosics, starches, and the like; and derivatives andmixtures thereof.

[0093] In embodiments in which the first portion is prepared viacompression, suitable disintegrants include sodium starch glycolate,cross-linked polyvinylpyrrolidone, cross-linked carboxymethylcellulose,starches, microcrystalline cellulose, and the like.

[0094] In embodiments in which the first portion is prepared viacompression, suitable lubricants include long chain fatty acids andtheir salts, such as magnesium stearate and stearic acid, talc, andwaxes.

[0095] In embodiments in which the first portion is prepared viacompression, suitable glidants include colloidal silicon dioxide, andthe like.

[0096] In embodiments in which the first portion is prepared viacompression, the dosage form of the invention may also incorporatepharmaceutically acceptable adjuvants, including, for example,preservatives, high intensity sweeteners such as aspartame, acesulfamepotassium, cyclamate, saccharin, sucralose, and the like; and othersweeteners such as dihydroalcones, glycyrrhizin, Monellin™, stevioside,Talin™, and the like; flavors, antioxidants, surfactants, and coloringagents.

[0097] The active ingredient or ingredients are preferably capable ofdissolution upon contact with a fluid such as water, stomach acid,intestinal fluid or the like. In a preferred embodiment the dissolutioncharacteristics of the active ingredient meet USP specifications forimmediate release tablets containing the active ingredient. Inembodiments in which it is desired for the active ingredient to beabsorbed into the systemic circulation of an animal, the activeingredient or ingredients are preferably capable of dissolution uponcontact with a fluid such as water, gastric fluid, intestinal fluid orthe like. In one embodiment, the dissolution characteristics of theactive ingredient meet USP specifications for immediate release tabletscontaining the active ingredient. For example, for acetaminophentablets, USP 24 specifies that in pH 5.8 phosphate buffer, using USPapparatus 2 (paddles) at 50 rpm, at least 80% of the acetaminophencontained in the dosage form is released therefrom within 30 minutesafter dosing, and for ibuprofen tablets, USP 24 specifies that in pH 7.2phosphate buffer, using USP apparatus 2 (paddles) at 50 rpm, at least80% of the ibuprofen contained in the dosage form is released therefromwithin 60 minutes after dosing. See USP 24, 2000 Version, 19-20 and 856(1999). In another embodiment, the dissolution characteristics of theactive ingredient are modified: e.g. controlled, sustained, extended,retarded, prolonged, delayed and the like.

[0098] An overall understanding of the dosage form of this invention maybe obtained by reference to FIGS. 1A, 1B, 2A and 2B. FIGS. 1A and 1Bdepict one embodiment of the dosage form of this invention. In FIG. 1A,a dosage form 2 is depicted which comprises a first portion 4. The firstportion comprises a plurality of debossments which in turn compriseinlaid second portions 6. In this embodiment, a first active ingredientis located within first portion 4 and a second active ingredient islocated within inlaid second portions 6. FIG. 1B is a cross-sectionalview of the dosage form 2 of FIG. 1A. As shown in FIG. 1B, in thisembodiment molded inlaid second portions 6 extend partially into thefirst portion 4 from both first surface 8 and second surface 10. In thisembodiment a first active ingredient is located within inlaid secondportions 6 and a second active ingredient (which may be the same ordifferent than the first active ingredient) is located within firstportion 4, although in other embodiments only one of inlaid secondportions 6 or first portion 4 may contain an active ingredient.

[0099] In other embodiments as depicted in FIGS. 1A and 1B, a clear orsemi-transparent coating may reside on first surface 8 and secondsurface 10.

[0100]FIGS. 2A and 2B depict another embodiment of this invention. FIG.2A depicts a dosage form 102 which comprises a core 104. The core has ashell 105 residing on at least a portion of the exterior surface of core104. The shell 105 is shown in greater detail in FIG. 2B, which is across-sectional view of the dosage form of FIG. 2A. As shown in FIG. 2B,the shell 105 residing on the exterior surfaces 108 and 110 of core 104comprises a first shell portion 107 having cavities, with molded inlaidsecond shell portions 106 residing in the cavities. In this embodiment,a first active ingredient is located within shell portion 107 and asecond active ingredient is located within inlaid second shell portions106, although in other embodiments only one of first shell portion 107or inlaid second shell portions 106 may contain an active ingredient.Core 104 may optionally also contain an active ingredient, which may bethe same or different than the active ingredient contained in firstshell portion 107 and inlaid second shell portions 106. As depicted inFIG. 2B, the shell 105 may extend along the side portions 112 and 114 ofcore 104, and inlaid portions 116 and 118 may reside in the indentationsof shell 105. In this embodiment, the cavities extend through the firstshell portion up to the surface of the core; however, in otherembodiments the cavities may only extend through a part of the firstshell portion.

[0101] The core (or substrate) may be any solid or semi-solid form. Thecore may prepared by any suitable method, for example the core be acompressed dosage form, or may be molded. As used herein, “substrate”refers to a surface or underlying support, upon which another substanceresides or acts, and “core” refers to a material which is at leastpartially enveloped or surrounded by another material. For the purposesof the present invention, the terms may be used interchangeably: i.e.the term “core” may also be used to refer to a “substrate.” Preferably,the core comprises a solid, for example, the core may be a compressed ormolded tablet, hard or soft capsule, suppository, or a confectioneryform such as a lozenge, nougat, caramel, fondant, or fat basedcomposition. In certain other embodiments, the core may be in the formof a semi-solid or a liquid in the finished dosage form.

[0102] The core may be in a variety of different shapes. For example, inone embodiment the core may be in the shape of a truncated cone. Inother embodiments the core may be shaped as a polyhedron, such as acube, pyramid, prism, or the like; or may have the geometry of a spacefigure with some non-flat faces, such as a cone, cylinder, sphere,torus, or the like. Exemplary core shapes which may be employed includetablet shapes formed from compression tooling shapes described by “TheElizabeth Companies Tablet Design Training Manual” (Elizabeth CarbideDie Co., Inc., p.7 (McKeesport, Pa.) (incorporated herein by reference)as follows (the tablet shape corresponds inversely to the shape of thecompression tooling):

[0103] 1. Shallow Concave.

[0104] 2. Standard Concave.

[0105] 3. Deep Concave.

[0106] 4. Extra Deep Concave.

[0107] 5. Modified Ball Concave.

[0108] 6. Standard Concave Bisect.

[0109] 7. Standard Concave Double Bisect.

[0110] 8. Standard Concave European Bisect.

[0111] 9. Standard Concave Partial Bisect.

[0112] 10. Double Radius.

[0113] 11. Bevel & Concave.

[0114] 12. Flat Plain.

[0115] 13. Flat-Faced-Beveled Edge (F.F.B.E.).

[0116] 14. F.F.B.E. Bisect.

[0117] 15. F.F.B.E. Double Bisect.

[0118] 16. Ring.

[0119] 17. Dimple.

[0120] 18. Ellipse.

[0121] 19. Oval.

[0122] 20. Capsule.

[0123] 21. Rectangle.

[0124] 22. Square.

[0125] 23. Triangle.

[0126] 24. Hexagon.

[0127] 25. Pentagon.

[0128] 26. Octagon.

[0129] 27. Diamond.

[0130] 28. Arrowhead.

[0131] 29. Bullet.

[0132] 30. Barrel.

[0133] 31. Half Moon.

[0134] 32. Shield.

[0135] 33. Heart.

[0136] 34. Almond.

[0137] 35. House/Home Plate.

[0138] 36. Parallelogram.

[0139] 37. Trapezoid.

[0140] 38. FIG. 8/Bar Bell.

[0141] 39. Bow Tie.

[0142] 40. Uneven Triangle.

[0143] The core or sub-core may optionally be at least partially coveredby a compressed, molded, or sprayed sub-coating. However, in onepreferred embodiment, the core may be substantially free of thesubcoating: i.e. there is no subcoating located between the outersurface of the core and the inner surface of the shell.

[0144] In another embodiment of this invention, the core is a compresseddosage form: i.e. a tablet, obtained from a compressed powder. Thepowder may preferably comprise an active ingredient, and optionallycomprise various excipients, such as binders, disintegrants, lubricants,fillers and the like, as is conventional, or the powder may compriseother particulate material of a medicinal or non-medicinal nature, suchas inactive placebo blends for tableting, confectionery blends, and thelike. One particular formulation comprises active ingredient, powderedwax (such as shellac wax, microcrystalline wax, polyethylene glycol, andthe like), and optionally disintegrants and lubricants and is describedin more detail at pages 4-11 of pending U.S. patent application Ser. No.09/966,493, the disclosure of which is incorporated herein by reference.

[0145] The core may optionally comprise a sub-core (which may also bereferred to as an “insert”), which may be made by any method, forexample compression or molding, and which may optionally contain one ormore active ingredients.

[0146] In one embodiment of the invention, the dosage forms of thisinvention comprise a core made from a blend of powders having an averageparticle size of about 50 to about 500 microns. In one embodiment, theactive ingredient has an average particle size of about 50 to about 500microns. In another embodiment, at least one excipient has an averageparticle size of about 50 to about 500 microns, e.g. about 100 to about500 microns. In one such embodiment, a major excipient, i.e. andexcipient comprising at least 50% by weight of the core, has an averageparticle size of about 50 to about 500 microns, e.g. about 100 to about500 microns. Particles in this size range are particularly useful fordirect compression processes. In a preferred embodiment of theinvention, the core may be prepared by a direct compression process.

[0147] In one such embodiment of the invention, the core is a directlycompressed tablet, made from a powder which is substantially free ofwater soluble polymeric binders and hydrated polymers. This compositionis advantageous for maintaining an immediate release dissolutionprofile, minimizing processing and material costs, and providing foroptimal physical and chemical stability of the dosage form.

[0148] In embodiments in which the core is prepared by directcompression, the materials comprising the core, e.g. the activeingredient or ingredients and excipients, are blended together,preferably as dry powders, and fed into an apparatus that appliespressure and forms a core. Any suitable compacting apparatus may beused, including for example a roller compactor such as a chilsonator ordrop roller; or a conventional tablet press. Preferably, the core isformed by compaction using a rotary tablet press as known in the art. Ina rotary tablet press, a metered volume of powder is filled into a diecavity, which rotates as part of a “die table” from the filling positionto a compaction position where the powder is compacted between an upperand a lower punch to an ejection position where the resulting tablet ispushed from the die cavity by the lower punch. The direct compressionprocess enables the minimization or elimination of water-soluble,non-saccharide polymeric binders such as polyvinyl pyrrolidone,alginates, hydroxypropyl cellulose, hydroxypropylmethylcellulose,hydroxyethylcellulose, and the like, which can have an adverse effect ondissolution.

[0149] In a preferred embodiment, the core is prepared by thecompression methods and apparatus described in copending U.S.application Ser. No. 09/966,509, pages 16-27, the disclosure of which isincorporated herein by reference. Specifically, the core is made using arotary compression module comprising a fill zone, insertion zone,compression zone, ejection zone, and purge zone in a single apparatushaving a double row die construction as shown in FIG. 6 of U.S.application Ser. No. 09/966,509. The dies of the compression module arepreferably filled using the assistance of a vacuum, with filters locatedin or near each die. The purge zone of the compression module includesan optional powder recovery system to recover excess powder from thefilters and return the powder to the dies.

[0150] In another embodiment, the core is prepared by a wet-granulationmethod, in which the active ingredient or ingredients, appropriateexcipients, and a solution or dispersion of a wet binder (e.g. anaqueous cooked starch paste, or solution of polyvinyl pyrrolidone) aremixed and granulated. Suitable apparatuses for wet granulation includelow shear, e.g. planetary mixers, high shear mixers, and fluid beds,including rotary fluid beds. The resulting granulated material is dried,and optionally dry-blended with further ingredients, e.g. adjuvantsand/or excipients such as for example lubricants, colorants, and thelike. The final dry blend is then suitable for compression by themethods described in the previous paragraph.

[0151] Methods for direct compression and wet granulation processes areknown in the art, and are described in detail in, for example, Lachman,et al., The Theory and Practice of Industrial Pharmacy, Chapter 11 (3rded. 1986).

[0152] In one embodiment, the first portion or core is prepared bythermal setting molding using the method and apparatus described incopending U.S. patent application Ser. No. 09/966,450, pages 57-63, thedisclosure of which is incorporated herein by reference. In thisembodiment, the first portion or core is formed by injecting a startingmaterial in flowable form into a molding chamber. The starting materialpreferably comprises an active ingredient and a thermal setting materialat a temperature above the melting point of the thermal setting materialbut below the decomposition temperature of the active ingredient. Thestarting material is cooled and solidifies in the molding chamber into ashaped form (i.e. having the shape of the mold).

[0153] In another embodiment, the first portion or core is prepared bythermal cycle molding using the method and apparatus described incopending U.S. patent application Ser. No. 09/966,497, pages 27-51, thedisclosure of which is incorporated herein by reference. In thisembodiment, the first portion or core is formed by injecting a startingmaterial in flowable form into a heated molding chamber. The startingmaterial preferably comprises an active ingredient and a thermoplasticmaterial at a temperature above the set temperature of the thermoplasticmaterial but below the decomposition temperature of the activeingredient. The starting material is cooled and solidifies in themolding chamber into a shaped form (i.e. having the shape of the mold).

[0154] According to this method, the starting material must be inflowable form. For example, it may comprise solid particles suspended ina molten matrix, for example a polymer matrix. The starting material maybe completely molten or in the form of a paste. The starting materialmay comprise an active ingredient dissolved in a molten material.Alternatively, the starting material may be made by dissolving a solidin a solvent, which solvent is then evaporated from the startingmaterial after it has been molded.

[0155] The starting material may comprise any edible material which isdesirable to incorporate into a shaped form, including activeingredients such as those active ingredients previously described withrespect to the core, nutritionals, vitamins, minerals, flavors,sweeteners, and the like. Preferably, the starting material comprises anactive ingredient and a thermal setting material. The thermal settingmaterial may be any edible material that is flowable at a temperaturebetween about 37 and about 250° C., and that is a solid or semi-solid ata temperature between about −10° C. and about 35° C. The flowablematerial may be any edible material that is flowable at a temperaturebetween about 37° C. and 250° C., and that is solid, semi-solid, or canform a gel at a temperature between about −10° C. and about 35° C. Whenit is in the fluid or flowable state, the flowable material may comprisea dissolved or molten component, and optionally a solvent such as forexample water or organic solvents, or combinations thereof. The solventmay be partially or substantially removed by drying. Suitable flowablematerials include those comprising thermal setting materials, filmforming polymers, gelling polymers, hydrocolloids, low meltinghydrophobic materials such as fats and waxes, non-crystallizablecarbohydrates, and the like. Preferred thermal setting materials includewater-soluble polymers such as polyalkylene glycols, polyethylene oxidesand derivatives, and sucrose esters; fats such as cocoa butter,hydrogenated vegetable oil such as palm kernel oil, cottonseed oil,sunflower oil, and soybean oil; free fatty acids and their salts; mono-di- and triglycerides, phospholipids, waxes such as carnuba wax,spermaceti wax, beeswax, candelilla wax, shellac wax, microcrystallinewax, and paraffin wax; fat-containing mixtures such as chocolate; sugarin the form on an amorphous glass such as that used to make hard candyforms, sugar in a supersaturated solution such as that used to makefondant forms; low-moisture polymer solutions such as mixtures ofgelatin and other hydrocolloids at water contents up to about 30% suchas those used to make “gummi” confection forms. In a particularlypreferred embodiment, the thermal setting material is a blend of fatsand mono- and diglycerides.

[0156] In another embodiment, the core may be a hollow or evacuatedcore. For example, the core may be an empty capsule shell.Alternatively, a hollow core may be prepared for example by molding. Inone such method, flowable material is injected into a mold cavity, thecavity is brought to a temperature at which the outer surface of thecore (which is in contact with the mold) begins to solidify or set. Theexcess flowable material from the center of the core is then withdrawnfrom the mold using suitable means, for example a piston pump. Inanother such method, an empty capsule is used as a sub-core, and acoating layer is formed thereon by methods known in the art such as, forexample, spray-coating, dip-coating, or thermal cycle molding asdescribed in copending U.S. patent application Ser. No. 09/966, 497,pages 27-51, the disclosure of which is incorporated herein byreference.

[0157] In certain embodiments of the invention, the core may furthercomprise a subcoating, applied by any method, for example spraying,compression, or molding. In certain other embodiments of the invention,the core may be substantially free of a subcoating.

[0158] In another embodiment of the invention, the core contains atleast in part one or more inserts. The inserts can be made in any shapeor size. For instance, irregularly shaped inserts can be made, that isshapes having no more than one axis of symmetry. Cylindrically shapedinserts may also be made. The insert may be made using conventionaltechniques such as panning, compression, or molding. In one embodiment,the insert is prepared using the thermal setting method and apparatus asdescribed herein.

[0159] In one embodiment of the invention, the insert may have anaverage diameter from about 100 to about 1000 microns. In anotherembodiment of this invention, the insert may have an average diameter orthickness from about 10% to about 90% of the diameter or thickness ofthe core. In yet another embodiment of this invention, the core maycomprise a plurality of inserts.

[0160] In another embodiment, the insert may have an average diameter,length, or thickness greater than about 90% of the diameter or thicknessof the core, for example the insert may have an average length greaterthan about 100% of the thickness of the core.

[0161] In another embodiment of the invention, the core, the insert (ifemployed), the inlaid portion or any combination thereof may comprise amicroelectronic device (e.g. an electronic “chip”) which may be used asan active component or to control, for example, the rate of release ofactive ingredients within the core or insert in response to an inputsignal. Examples of such microelectronic devices are as follows:

[0162] (1) Integrated, self-regulating responsive therapeutic devicesincluding biosensors, electronic feedback and drug/countermeasurerelease devices which are fully integrated. Such devices eliminate theneed for telemetry and human intervention, and are disclosed, forexample, at www.chiprx.com/products.html, which is incorporated hereinby reference;

[0163] (2) Miniaturized diagnostic imaging systems which comprise aswallowable capsule containing a video camera, and are disclosed, forexample, at www.givenimaging.com/usa/default.asp, which is incorporatedherein by reference;

[0164] (3) Subcutaneous glucose monitors which comprise implantable orinsertable sensor devices which detect changes in glucose concentrationwithin intestinal fluid, and communicate to an external detector anddata storage device. Such devices are disclosed, for example, atwww.applied-medical.co.uk/glucose.htm, which is incorporated herein byreference;

[0165] (4) Microdisplay vision aid devices encapsulated in an artificialintraocular lens. Such devices include a receiver for power supply, dataand clock recovery, and a miniature LED array flip-chip bonded to asilicon CMOS driver circuit and micro optics, and are disclosed, forexample, at http://ios.oe.uni-duisberg.de/e/, which is incorporatedherein by reference. The microdisplay device receives abit-stream+energy wireless signal from a high dynamic range CMOS cameraplaced outside the eye which generates a digital black & white picturewhich is converted by a digital signal processing unit (DAP) into aserial bit-stream with a data rate of approximately 1 Mbit/s. The imageis projected onto the retina;

[0166] (5) Microchips used to stimulate damaged retinal cells, allowingthem to send visual signals to the brain for patients with maculardegeneration or other retinal disorders. The chip is 2 mm×25 microns,and contains approximately 5,000 microscopic solar cells(“microphotodiodes”), each with its own stimulating electrode. Thesemicrophotodiodes convert the light energy from images into electricalchemical impulses that stimulate the remaining functional cells of theretina in patients with AMD and RP. Such microchips are disclosed, forexample, at www.optobionics.com/artificialretina.htm, which isincorporated herein by reference;

[0167] (6) Disposable “smart needles” for breast biopsies which displayresults in real time. The device fits into a 20 to 21 gauge disposableneedle that is connected to a computer, as the needle is inserted intothe suspicious lesion. The device measures oxygen partial pressure,electrical impedance, temperature, and light scattering and absorptionproperties including deoxygenated hemoglobin, vascularization, andtissue density. Because of the accuracy benefits from the sixsimultaneous measurements, and real-time nature of the device, it isexpected to exceed the accuracy levels achieved by the core needlebiopsy procedure and approach the high level of accuracy associated withsurgical biopsies. Further, if cancer is found, the device can beconfigured to deliver various therapies such as cancer markers, laserheat, cryogenics, drugs, and radioactive seeds. Such devices aredisclosed, for example, at www.bioluminate.com/description.html, whichis incorporated herein by reference; and

[0168] (7) Personal UV-B recorders, which are instrument grade devicesfor measuring and recording UVB exposure and fit into a wrist-watchface. They may also be worn as a patch.

[0169] In one embodiment of the invention, the shell or inlaid portionor both are made from a flowable material.

[0170] The inlaid portion must be molded. In a preferred embodiment ofthe invention, the inlaid portion is prepared using thermal settingmolding or thermal cycle molding as described above.

[0171] The inlaid portion of the present invention may comprise anymaterial which can be molded, including for example, film formers,low-melting hydrophobic materials, gelling polymers, thickeners,plasticizers, adjuvants, and excipients.

[0172] In one embodiment, the inlaid portion preferably comprises atleast about 50%, preferably at least about 80%, most preferably at leastabout 90% of a material selected from film formers, gelling polymers,low-melting hydrophobic materials, non-crystallizable sugars or sugaralcohols, and mixtures thereof. In another embodiment, the inlaidportion comprises at least about 50%, preferably at least about 80%,most preferably at least about 90% of a material selected from filmformers, gelling polymers, low-melting hydrophobic materials, andmixtures thereof.

[0173] In one embodiment of the invention, the flowable materialcomprises gelatin as a gelling polymer. Gelatin is a natural,thermogelling polymer. It is a tasteless and colorless mixture ofderived proteins of the albuminous class which is ordinarily soluble inwarm water. Two types of gelatin—Type A and Type B—are commonly used.Type A gelatin is a derivative of acid-treated raw materials. Type Bgelatin is a derivative of alkali-treated raw materials. The moisturecontent of gelatin, as well as its Bloom strength, composition andoriginal gelatin processing conditions, determine its transitiontemperature between liquid and solid. Bloom is a standard measure of thestrength of a gelatin gel, and is roughly correlated with molecularweight. Bloom is defined as the weight in grams required to move ahalf-inch diameter plastic plunger 4 mm into a 6.67% gelatin gel thathas been held at 10° C. for 17 hours. In a preferred embodiment, theflowable material is an aqueous solution comprising 20% 275 Bloom porkskin gelatin, 20% 250 Bloom Bone Gelatin, and approximately 60% water.

[0174] Other preferred flowable materials may comprise sucrose-fattyacid esters; fats such as cocoa butter, hydrogenated vegetable oil suchas palm kernel oil, cottonseed oil, sunflower oil, and soybean oil; freefatty acids and their salts; mono- di- and triglycerides, phospholipids,waxes such as carnuba wax, spermaceti wax, beeswax, candelilla wax,shellac wax, microcrystalline wax, and paraffin wax; fat-containingmixtures such as chocolate; sugar in the form on an amorphous glass suchas that used to make hard candy forms, sugar in a supersaturatedsolution such as that used to make fondant forms; carbohydrates such assugar-alcohols (for example, sorbitol, maltitol, mannitol, xylitol anderythritol), or thermoplastic starch; and low-moisture polymer solutionssuch as mixtures of gelatin and other hydrocolloids at water contents upto about 30%, such as for example those used to make “gummi” confectionforms.

[0175] In one embodiment of the invention, the flowable material maycomprise a film former such as a cellulose ether, e.g.hydroxypropylmethylcellulose or a modified starch, e.g. waxy maizestarch; optionally an extender, such as polycarbohydrates, e.g.maltodextrin; optionally a thickener, such as a hydrocolloid, e.g.xanthan gum or carrageenan, or a sugar, e.g. sucrose; optionally aplasticizer, e.g. polyethylene glycol, propylene glycol, vegetable oilssuch as castor oil, glycerin, and mixtures thereof.

[0176] Any film former known in the art is suitable for use in theflowable material. Examples of suitable film formers include, but arenot limited to, polyvinylalcohol (PVA), polyvinylpyrrolidone (PVP),hydroxypropyl starch, hydroxyethyl starch, pullulan, methylethyl starch,carboxymethyl starch, methylcellulose, hydroxypropylcellulose (HPC),hydroxyethylmethylcellulose (HEMC), hydroxypropylmethylcellulose (HPMC),hydroxybutylmethylcellulose (HBMC), hydroxyethylethylcellulose (HEEC),hydroxyethylhydroxypropylmethyl cellulose (HEMPMC), methacrylic acid andmethacrylate ester copolymers, polyethylene oxide andpolyvinylpyrrolidone copolymers, gelatin, proteins such as whey protein,coaggulatable proteins such as albumin, casein, and casein isolates, soyprotein and soy protein isolates, pre-gelatinized starches, and polymersand derivatives and mixtures thereof.

[0177] One suitable hydroxypropylmethylcellulose compound is HPMC 2910,which is a cellulose ether having a degree of substitution of about 1.9and a hydroxypropyl molar substitution of 0.23, and containing, basedupon the total weight of the compound, from about 29% to about 30%methoxyl groups and from about 7% to about 12% hydroxylpropyl groups.HPMC 2910 is commercially available from the Dow Chemical Company underthe tradename METHOCEL E. METHOCEL E5, which is one grade of HPMC-2910suitable for use in the present invention, has a viscosity of about 4 to6 cps (4 to 6 millipascal-seconds) at 20° C. in a 2% aqueous solution asdetermined by a Ubbelohde viscometer. Similarly, METHOCEL E6, which isanother grade of HPMC-2910 suitable for use in the present invention,has a viscosity of about 5 to 7 cps (5 to 7 millipascal-seconds) at 20°C. in a 2% aqueous solution as determined by a Ubbelohde viscometer.METHOCEL E15, which is another grade of HPMC-2910 suitable for use inthe present invention, has a viscosity of about 15000 cps (15millipascal-seconds) at 20° C. in a 2% aqueous solution as determined bya Ubbelohde viscometer. As used herein, “degree of substitution” shallmean the average number of substituent groups attached to aanhydroglucose ring, and “hydroxypropyl molar substitution” shall meanthe number of moles of hydroxypropyl per mole anhydroglucose.

[0178] As used herein, “modified starches” include starches that havebeen modified by crosslinking, chemically modified for improvedstability, or physically modified for improved solubility properties. Asused herein, “pre-gelatinized starches” or “instantized starches” refersto modified starches that have been pre-wetted, then dried to enhancetheir cold-water solubility. Suitable modified starches are commerciallyavailable from several suppliers such as, for example, A. E. StaleyManufacturing Company, and National Starch & Chemical Company. Onesuitable modified starch includes the pre-gelatinized waxy maizederivative starches that are commercially available from National Starch& Chemical Company under the tradenames PURITY GUM and FILMSET, andderivatives, copolymers, and mixtures thereof. Such waxy maize starchestypically contain, based upon the total weight of the starch, from about0 percent to about 18 percent of amylose and from about 100% to about88% of amylopectin.

[0179] Suitable tapioca dextrins include those available from NationalStarch & Chemical Company under the tradename CRYSTAL GUM or K-4484, andderivatives thereof such as modified food starch derived from tapioca,which is available from National Starch and Chemical under the tradenamePURITY GUM 40, and copolymers and mixtures thereof.

[0180] Any thickener known in the art is suitable for use in theflowable material. Examples of such thickeners include but are notlimited to hydrocolloids (also referred to herein as gelling polymers)such as alginates, agar, guar gum, locust bean, carrageenan, tara, gumarabic, tragacanth, pectin, xanthan, gellan, maltodextrin,galactomannan, pusstulan, laminarin, scleroglucan, gum arabic, inulin,pectin, whelan, rhamsan, zooglan, methylan, chitin, cyclodextrin,chitosan, and derivatives and mixtures thereof. Additional suitablethickeners include crystallizable carbohydrates, and the like, andderivatives and combinations thereof. Suitable crystallizablecarbohydrates include the monosaccharides and the oligosaccharides. Ofthe monosaccharides, the aldohexoses e.g., the D and L isomers ofallose, altrose, glucose, mannose, gulose, idose, galactose, talose, andthe ketohexoses e.g., the D and L isomers of fructose and sorbose alongwith their hydrogenated analogs: e.g., glucitol (sorbitol), and mannitolare preferred. Of the oligosaccharides, the 1,2-disaccharides sucroseand trehalose, the 1,4-disaccharides maltose, lactose, and cellobiose,and the 1,6-disaccharides gentiobiose and melibiose, as well as thetrisaccharide raffinose are preferred along with the isomerized form ofsucrose known as isomaltulose and its hydrogenated analog isomalt. Otherhydrogenated forms of reducing disaccharides (such as maltose andlactose), for example, maltitol and lactitol are also preferred.Additionally, the hydrogenated forms of the aldopentoses: e.g., D and Lribose, arabinose, xylose, and lyxose and the hydrogenated forms of thealdotetroses: e.g., D and L erythrose and threose are preferred and areexemplified by xylitol and erythritol, respectively.

[0181] Suitable xanthan gums include those available from C.P. KelcoCompany under the tradename KELTROL 1000, XANTROL 180, or K9B310.

[0182] Suitable thermoplastic materials can be molded and shaped whenheated, and include both water soluble and water insoluble polymers thatare generally linear, not crosslinked, nor strongly hydrogen bonded toadjacent polymer chains. Examples of suitable thermoplastic materialsinclude: chemically modified cellulose derivatives such as hydroxypropylcellulose (HPC), hydroxypropylmethyl cellulose (HPMC), methyl cellulose(MC), cellulose acetate (CA), ethyl cellulose (EC), cellulose acetatebutyrate (CAB), cellulose propionate; vinyl polymers such as polyvinylalcohol (PVA) and polyvinyl pyrrolidone (PVP); thermoplastic starch;natural and chemically modified proteins such as gelatin, soy proteinisolates, whey protein, myofibrillar proteins, and the milk derivedcaseinate proteins; and derivatives and combinations thereof.

[0183] Any plasticizer known in the pharmaceutical art is suitable foruse in the present invention, and may include, but not be limited topolyethylene glycol; glycerin; sorbitol; triethyl citrate; tribuylcitrate; dibutyl sebecate; vegetable oils such as castor oil;surfactants such as polysorbates, sodium lauryl sulfates, anddioctyl-sodium sulfosuccinates; propylene glycol; mono acetate ofglycerol; diacetate of glycerol; triacetate of glycerol; natural gumsand mixtures thereof. In solutions containing a cellulose ether filmformer, an optional plasticizer may be present in an amount, based uponthe total weight of the solution, from about 0% to about 40%.

[0184] The flowable material may optionally comprise adjuvants orexcipients, which may comprise up to about 20% by weight of the flowablematerial. Examples of suitable adjuvants or excipients includedetackifiers, humectants, surfactants, anti-foaming agents, colorants,flavorants, sweeteners, opacifiers, and the like. In one preferredembodiment, the flowable material comprises less than 5% humectants, oralternately is substantially free of humectants, such as glycerin,sorbitol, maltitol, xylitol, or propylene glycol. Humectants havetraditionally been included in pre-formed films employed in enrobingprocesses, such as that disclosed in U.S. Pat. Nos. 5,146,730 and5,459,983 to ensure adequate flexibility or plasticity and bondabilityof the film during processing. Humectants function by binding water andretaining it in the film. Pre-formed films used in enrobing processescan typically comprise up to 45% water. Disadvantageously, the presenceof humectant prolongs the drying process, and can adversely affect thestability of the finished dosage form.

[0185] In a preferred embodiment of the invention, the inlaid portion ofthe dosage form comprises at least about 80%, preferably at least about90% of a material selected from film formers, gelling polymers(hydrocolloids), thermoplastic materials, low-melting hydrophobicmaterials, non-crystallizable sugars, and mixtures thereof. The inlaidportion may be formed by injection molding, advantageously minimizing oreliminating the need for direct-compression filler-binders such asmicrocrystalline cellulose, spray-dried lactose, mineral salts such ascalcium phosphate, crystalline sugars such as sucrose, dextrates and thelike. These materials would disadvantageously detract from the clarityand stability of the inlaid portion. Preferably the inlaid portion ofthe present invention comprises less than about 10%, e.g. less thanabout 1%, or less than about 0.1% of direct-compression filler-binders.The inlaid portion used in the present invention are thus an improvementover compression-coated shells, which typically comprise at least about30% of a direct-compression filler-binder. See, for example, WO00/18447.

[0186] The inlaid portion may be prepared by molding, as discussedabove.

[0187] In one embodiment of the invention, the inlaid portion comprisesa modified release composition as described in U.S. patent applicationSer. No. ______ (WO/______) [MCP320], the disclosure of which isincorporated herein by reference.

[0188] In another embodiment of the invention, the inlaid portioncomprises any of the modified release compositions described in U.S.patent application Ser. Nos. ______ or ______ (WO/______ or WO/______)[MCP322 and 323], the disclosures of which are incorporated herein byreference.

[0189] In a preferred embodiment, the inlaid portion is substantiallyfree of pores having a diameter of 0.5-5.0 microns. As used herein,“substantially free” means that the inlaid portion has a pore volume ofless than about 0.02 cc/g, preferably less than about 0.01 cc/g, morepreferably less than about 0.005 cc/g, in the pore diameter range of 0.5to 5.0 microns. Typical compressed materials have pore volumes of morethan about 0.02 cc/g in this pore diameter range. Pore volume, porediameter and density may be determined using a Quantachrome InstrumentsPoreMaster 60 mercury intrusion porosimeter and associated computersoftware program known as “Porowin.” The procedure is documented in theQuantachrome Instruments PoreMaster Operation Manual. The PoreMasterdetermines both pore volume and pore diameter of a solid or powder byforced intrusion of a non-wetting liquid (mercury), which involvesevacuation of the sample in a sample cell (penetrometer), filling thecell with mercury to surround the sample with mercury, applying pressureto the sample cell by: (i) compressed air (up to 50 psi maximum); and(ii) a hydraulic (oil) pressure generator (up to 60000 psi maximum).Intruded volume is measured by a change in the capacitance as mercurymoves from outside the sample into its pores under applied pressure. Thecorresponding pore size diameter (d) at which the intrusion takes placeis calculated directly from the so-called “Washburn Equation”:d=−(4γ(cos θ))/P where γ is the surface tension of liquid mercury, θ isthe contact angle between mercury and the sample surface and P is theapplied pressure.

[0190] Equipment used for pore volume measurements:

[0191] 1. Quantachrome Instruments PoreMaster 60.

[0192] 2. Analytical Balance capable of weighing to 0.0001 g.

[0193] 3. Desiccator.

[0194] Reagents used for measurements:

[0195] 1. High purity nitrogen.

[0196] 2. Triply distilled mercury.

[0197] 3. High pressure fluid (Dila AX, available from Shell ChemicalCo.).

[0198] 4. Liquid nitrogen (for Hg vapor cold trap).

[0199] 5. Isopropanol or methanol for cleaning sample cells.

[0200] 6. Liquid detergent for cell cleaning.

[0201] Procedure:

[0202] The samples remain in sealed packages or as received in thedessicator until analysis. The vacuum pump is switched on, the mercuryvapor cold trap is filled with liquid nitrogen, the compressed gassupply is regulated at 55 psi., and the instrument is turned on andallowed a warm up time of at least 30 minutes. The empty penetrometercell is assembled as described in the instrument manual and its weightis recorded. The cell is installed in the low pressure station and“evacuation and fill only” is selected from the analysis menu, and thefollowing settings are employed:

[0203] Fine Evacuation time: 1 min.

[0204] Fine Evacuation rate: 10

[0205] Coarse Evacuation time: 5 min.

[0206] The cell (filled with mercury) is then removed and weighed. Thecell is then emptied into the mercury reservoir, and two tablets fromeach sample are placed in the cell and the cell is reassembled. Theweight of the cell and sample are then recorded. The cell is theninstalled in the low-pressure station, the low-pressure option isselected from the menu, and the following parameters are set:

[0207] Mode: Low pressure

[0208] Fine evacuation rate: 10

[0209] Fine evacuation until: 200% Hg

[0210] Coarse evacuation time: 10 min.

[0211] Fill pressure: Contact +0.1

[0212] Maximum pressure: 50

[0213] Direction: Intrusion And Extrusion

[0214] Repeat: 0

[0215] Mercury contact angle; 140

[0216] Mercury surface tension: 480

[0217] Data acquisition is then begun. The pressure vs. cumulativevolume-intruded plot is displayed on the screen. After low-pressureanalysis is complete, the cell is removed from the low-pressure stationand reweighed. The space above the mercury is filled with hydraulic oil,and the cell is assembled and installed in the high-pressure cavity. Thefollowing settings are used:

[0218] Mode: Fixed rate

[0219] Motor speed: 5

[0220] Start pressure: 20

[0221] End pressure: 60,000

[0222] Direction: Intrusion and extrusion

[0223] Repeat: 0

[0224] Oil fill length: 5

[0225] Mercury contact angle: 140

[0226] Mercury surface tension: 480

[0227] Data acquisition is then begun and graphic plot pressure vs.intruded volume is displayed on the screen. After the high pressure runis complete, the low- and high-pressure data files of the same sampleare merged.

[0228] In one embodiment of the invention, only the core comprises oneor more active ingredients. In another embodiment of this invention,only the inlaid portion comprises one or more active ingredients. In yetanother embodiment of this invention, only the insert comprises one ormore active ingredients. In yet another embodiment of this invention,both the core and inlaid portion comprise one or more activeingredients. In yet another embodiment of this invention, one or more ofthe core, the inlaid portion, or the insert comprises one or more of theactive ingredients.

[0229] One of the advantages of this invention is that the inlaidportion may have a complex geometry or pattern. For example, inserts orinlaid portions previously disclosed in the prior art typically havebeen limited to simple shapes, e.g. shapes having circularcross-sections. Using prior art techniques, it would be extremelydifficult to press fit a complex logo, for example an intagliation thatcauses or requires discontinuities in the surface of the substrate,core, or first portion into which it must fit. However, because theinsert or inlaid portion of the present invention is obtained using aflowable material, it may be used to fill any depression in any shape orcontinuous pattern, or even a discontinuous pattern if multiple nozzlesare employed.

[0230] A particular advantage of the present invention is that theinserts or inlaid portions may be larger in cross-section (in at leastone portion) than the cavity which contains the insert or inlaidportion. For example, in one embodiment in which a second molded portionis inlaid into one or more cavities in the exterior surface of a firstportion of the dosage form, the area of at least one cross-section ofthe second molded inlaid portion is greater than the cross-sectionalarea of the cavity at the surface of the first portion. In contrast, inthe prior art an insert must be no larger in cross-section than theopening of the cavity which contains the insert. This may also beexpressed in terms of the “draft angle” of the insert or inlaid portion.As used herein, the term “draft angle” refers to the angle defined bythe side wall of the cavity and a line perpindicular to the face of thefirst portion, as described for example in Rosato et al., InjectionMolding Handbook, pp. 601-04, (2d ed. 1995), the disclosure of which isincorporated herein by reference. This is illustrated in FIGS. 3A and 3Bherein. In FIG. 3A, a prior art insert 300 is shown being inserted intoa cavity 302 of core 304. The draft angle θ is defined by theperpendicular 306 and the sidewall 307. In the prior art, θ must have azero or positive value. However, in this present invention θ may have avalue less than zero.

[0231] In contrast, in FIG. 3B an insert or inlaid portion 500 as inthis invention is shown being inserted into a cavity 502 of core 504.The draft angle θ defined by the perpendicular ray 506 emerging from thepoint of intersection of cavity 502 and core 504 and the side face 508of insert 500 is less than 0°, as shown. This is because the first end509 of insert 500 is wider than cavity 502. However, insert 500 may fillcavity 502 due to its being composed of a flowable material. Thus,insert 500 may be “keyed” or interlocked into cavity 502.

[0232] This invention will be further illustrated by the followingexamples, which are not meant to limit the invention in any way.

EXAMPLE 1

[0233] Dosage forms of the invention are made in a continuous processusing an apparatus comprising a compression module and two thermal cyclemolding modules linked in series via first and second transfer devicesas described at pages 14-16 of copending U.S. application Ser. No.09/966,939, the disclosure of which is incorporated herein by reference.The dosage forms comprise a compressed core on which resides a shellcomprising a first shell portion and a second shell portion that form aninlaid pattern.

[0234] The core is made from a mixture of the following ingredients:acetaminophen USP (590 mg/tablet), synthetic wax X-2068 T20 (53mg/tablet), sodium starch glycolate (EXPLOTAB) (13.9 mg/tablet), silicondioxide (0.6 mg/tablet), and magnesium stearate NF (2.4 mg/tablet).These ingredients are made into a dry blend, which is compressed intocores on a compression module as described in copending U.S. applicationSer. No. 09/966,509 at pages 16-27 (incorporated herein by reference)using {fraction (7/16)} inch extra deep concave tablet tooling. Thecompression module is a double row, rotary apparatus, comprising a fillzone, insertion zone, compression zone, ejection zone, and purge zone asshown in FIG. 6 of U.S. application Ser. No. 09/966,509. The dies of thecompression module are filled using vacuum assistance, with mesh screenfilters located in die wall ports of each die. The resulting cores havean average weight of 660 mg, thickness of 0.306 inches, and hardness of3.2 kp.

[0235] The cores are conveyed to a first thermal cycle molding module asdescribed in copending U.S. application Ser. No. 09/966,497 at pages27-51 via a first transfer device as described in copending U.S.application Ser. No. 09/966,414 at pages 51-57, the disclosure of whichis incorporated herein by reference. Both the first and second transferdevices have the structure shown as 300 in FIG. 3 of copending U.S.application Ser. No. 09/966,414, and transfer the cores form thecompression module to the first thermal cycle molding module and fromthe first thermal cycle molding module to the second thermal cyclemolding module, respectively. They comprise a plurality of transferunits 304 attached in cantilever fashion to a belt 312 as shown in FIGS.68 and 69 of copending U.S. application Ser. No. 09/966,414. The firsttransfer device rotates and operates in sync with the compression moduleand the first thermal cycle molding module to which it is coupled. Thesecond transfer device rotates and operates in sync with the firstthermal cycle molding module and the second thermal cycle molding moduleto which it is coupled. Transfer units 304 comprise retainers 330 forholding the cores as they travel around the transfer devices.

[0236] The tablets are coated with a first shell portion comprising redgelatin in the first thermal cycle molding module. It is of the typeshown in FIG. 28A of copending U.S. application Ser. No. 09/966,939. Themold units 204 of the thermal cycle molding module comprise upper moldassemblies 214, rotatable center mold assemblies 212 and lower moldassemblies 210 as shown in FIG. 28C. Cores are transferred to the moldassemblies, which then close over the cores such that an inlaid patternover the core is masked by the interior surface of the mold assemblies,leaving exposed a mirror image inlaid pattern on the surface of thecores. First shell flowable material, as described below, which isheated to a flowable state in a reservoir 206, is injected into the moldcavities created by the closed mold assemblies. Due to the masking, itis applied only to the exposed portions of the core. The temperature ofthe first shell flowable material is then decreased, hardening it. Themold assemblies open and eject the partially coated cores to the secondtransfer device, which transfers them to the second thermal cyclemolding module.

[0237] The first shell portion comprises red gelatin coating, and ismade of the following ingredients: purified water, Opatint Red DD-1761,Opatint Yellow DD-2125, and 275 Bloom Pork Skin Gelatin and 250 BloomBone Gelatin (150 g) added together as a mix of dry gelatin granules. Agelatin slurry is formed from these ingredients and heated to 55° C. tomelt and dissolve the gelatin. The gelatin solution is held at 55° C.for approximately 3 hours (holding times at this temperature cangenerally range between about 2 and about 16 hours). The solution isthen mixed until uniform (about 5 to 15 minutes). The gelatin solutionis maintained at 55° C. with continuous mixing during its use in thefirst thermal cycling molding module.

[0238] The second thermal cycle molding module is also of the type shownin FIG. 26A of copending U.S. application Ser. No. 09/966,497. Itapplies the second shell portion (made from purified water (450 g),Opatint Yellow DD-2125 (6.2 g), 275 Bloom Pork Skin Gelatin (150 g) and250 Bloom Bone Gelatin (150 g) in the same manner as the first shellportion) to the cores. The upper and center mold assemblies of thesecond thermal cycle molding module mate such that the previouslyexposed portion of the core, now coated with the first shell portion,are masked. This exposes the previously masked portions of the core,which remain uncoated. Second flowable material, which is heated to aflowable state in reservoir 206, is then injected into the mated upperand center mold assemblies. The temperature of the second flowablematerial is then decreased, hardening the second flowable material toform an inlaid pattern. The mold assemblies open and eject the finisheddosage forms.

[0239] Although this invention has been illustrated by reference tospecific embodiments, it will be apparent to those skilled in the artthat various changes and modifications may be made which clearly fallwithin the scope of this invention.

The invention claimed is:
 1. A dosage form comprising at least oneactive ingredient, a first portion which comprises an exterior surfaceand one or more cavities defining at least one interior surface havingindentations, and a second molded portion which is inlaid into thecavities of the first portion and has an exterior surface, wherein thefirst and second portions are in contact at an interface, the secondportion comprises a solidified thermoplastic material, and the secondportion resides substantially conformally upon the indentations.
 2. Thedosage form of claim 1, wherein the second molded portion issubstantially free of pores having a diameter of 0.5 to 5.0 microns. 3.The dosage form of claim 1, wherein the first and second portions are inintimate contact at the interface.
 4. The dosage form of claim 1,wherein the first portion is a compressed tablet.
 5. The dosage form ofclaim 1, wherein the first portion is a molded tablet.
 6. The dosageform of claim 1 wherein the first portion comprises an intagliation andthe second portion resides in the intagliation.
 7. The dosage form ofclaim 1 wherein the exterior surface of the second portion is flush withthe exterior surface of the first portion.
 8. The dosage form of claim 1wherein the exterior surface of the second portion is raised withrespect to the exterior surface of the first portion.
 9. The dosage formof claim 1 wherein the first portion consists essentially of a singlehomogeneous layer.
 10. The dosage form of claim 1, in which the secondmolded portion comprises at least one active ingredient.
 11. The dosageform of claim 1, in which the first portion has a first color and theinlaid second portion has a second color.
 12. The dosage form of claim1, in which the first portion comprises a first active ingredient andthe inlaid second portion comprises a second active ingredient which maybe the same or different than the first active ingredient.
 13. Thedosage form of claim 1, in which the first and second portions togetherprovide a prearranged pattern.
 14. The dosage form of claim 1, in whichthe first portion comprises a microelectronic device.
 15. The dosageform of claim 1, in which the interior surface of one or more cavitiesin the first portion has a draft angle having a value less than zero.16. The dosage form of claim 1, in which the interface is substantiallycoextensive with the interior surface.
 17. The dosage form of claim 1,in which the first portion is discontinuous and the second portion iscontinuous.
 18. A dosage form comprising at least one active ingredient,a core having an outer surface and a shell residing on at least aportion of the core outer surface, wherein the shell comprises a firstshell portion and a second molded shell portion which is inlaid into thefirst shell portion, and the first and second shell portions are incontact at an interface.
 19. The dosage form of claim 18, in which theshell has an outer surface and the second molded shell portion extendsfrom the outer surface of the core to the outer surface of the shell.20. The dosage form of claim 18, in which the first and second shellportions are discontinuous.
 21. The dosage form of claim 18, in whichthe first shell portion has a first color and the second shell portionhas a second color.
 22. The dosage form of claim 18, in which the corecomprises a compressed powder.
 23. The dosage form of claim 18, in whichthe core comprises an insert.
 24. The dosage form of claim 23, in whichthe insert comprises an active ingredient.
 25. The dosage form of claim24, in which one or more of the core, the inlaid portion or the insertcomprise an active ingredient.
 26. The dosage form of claim 18, in whichthe core comprises a microelectronic device.
 27. The dosage form ofclaim 23, in which the insert comprises a microelectronic device. 28.The dosage form of claim 18, in which either the first shell portion,second shell portion, or both have a textured outer surface.
 29. Thedosage form of claim 18, in which the outer surface of the shellcontains a prearranged pattern.
 30. The dosage form of claim 18, inwhich the shell comprises one or more openings therein.
 31. The dosageform of claim 18, in which the outer surface of the shell issubstantially smooth.
 32. The dosage form of claim 18, in which theshell contains indentations, letters, symbols or a pattern.
 33. Thedosage form of claim 18, in which the first shell portion containsindentations, letters, symbols or a pattern.
 34. The dosage form ofclaim 18, in which the second shell portion contains indentations,letters, symbols or a pattern.
 35. The dosage form of claim 18, in whichthe first shell portion, second shell portion or both contain raisedprotrusions in the form of letters, symbols or a pattern.
 36. The dosageform of claim 18, in which the inlaid portion is substantially free ofpores having a diameter of 0.5-5.0 microns.
 37. The dosage form of claim18, in which the first shell portion has a draft angle having a valueless than zero at the interface.
 38. A dosage form comprising at leastone active ingredient, a core, and a shell having a first molded shellportion which is discontinuous, and a second molded shell portion whichis continuous, such that the discontinuities of the first shell portionare due to the presence of the second molded shell portion, and thefirst and second shell portions are compositionally different.
 39. Thedosage form of claim 18, wherein the first and second shell portionscomprise a solidified thermoplastic material.
 40. The dosage form claim18, wherein the exterior surfaces of the first and second shell portionsare coplanar.
 41. The dosage form of claim 1, wherein the cavitiesdefine a plurality of side walls for receiving the inlaid portion, andthe side walls have a draft angle less than zero.
 42. The dosage form ofclaim 1, wherein the area of at least one cross-section of the secondmolded inlaid portion is greater than the cross-sectional area of thecavity at the surface of the first portion.